1. Field of the Invention
This invention relates to a method of treating Alzheimer""s disease and more specifically relates to delivering therapeutic nonsteroidal anti-inflammatory agents directly into the central nervous system or specific brain structures.
2. Description of the Related Art
Studies support an inverse relationship between anti-inflammatory medications used for treating patients with rheumatoid arthritis and an associated low prevalence of Alzheimer""s disease [J. B. Rich et.al., Neurology 45:51-55, 1995]. Controlled studies of twin pairs having Alzheimer""s disease onset greater than 3 years provide additional support that prior treatment with anti-inflammatory medications serves a protective role in Alzheimer""s disease. [J. C. S. Breitner, et.,al., Neurology 44:227-232, 1994] Specifically, controlled double-blinded studies have found that the anti-inflammatory agent xe2x80x9cindomethacinxe2x80x9d administered orally has a therapeutic benefit for mild to moderately cognitively impaired Alzheimer""s disease patients, and treatment with indomethacin during early stages of the disease has a retarding affect on disease progression compared to the placebo treated control group. [J. Rogers, et.al., Neurology 43:1609-1612. 1993] Alzheimer""s patients with moderate cognitive impairment treated with indomethacin also exhibit a reduction in cognitive decline. However, patients treated with oral indomethacin developed drug related adverse effects that required their treatment to be discontinued and their removal from the study.
Studies have shown indomethacin works at the cellular areas of the brain affected by Alzheimer""s disease. These cellular areas include the hippocampus, entorhinal cortex, basal forebrain, amygdala and nucleus basalis of Meynert. In the normal brain, various enzyme systems act on amyloid precursor proteins to form peptides required for physiological brain functions including cellular membrane repair.
An example of normal amyloid protein processing is the action of an endoprotease termed xe2x80x9calpha-secretase.xe2x80x9d Alpha-secretase cleaves the amyloid precursor protein resulting in non-amyloidogenic peptide fragments. These non-amyloidogenic peptide fragments are required for normal cellular function (S. B. Roberts et.al., Journal of Biological Chemistry 269:3111-3116, 1994).
Other endoproteases, termed xe2x80x9cbeta-xe2x80x9d and xe2x80x9cgamma-secretasesxe2x80x9d, cleave the amyloid precursor protein to form amyloidogenic fragments capable of interacting with several other cellular proteins. The interaction of the amyloidogenic fragments and other cellular proteins forms enzymes that become the foci of neurotoxicity and subsequently neuritic plaques ( P. Eikelenboom, et.al., TiPS 15:447-450, 1994). In particular, beta-secretase cleaves the amyloid precursor protein to form fragments that result in increased calcium influx into the affected neurons. This increased calcium influx affects the intracellular pH and cytokine induction of the neurons which triggers intracellular enzymatic activation including lipoxygenase and cyclooxygenase up-regulation.
These enzymes resulting from the interaction of the amyloidogenic fragments and other cellular proteins further disrupt intracellular microtubule metabolism with inhibition of protein transport blocking neurotransmission along the neurite""s axon. The result of this process is senile neuritic plaque formation and neurofibrillary tangles associated with Alzheimer""s disease.
Although the specific causes for increased cellular production of altered secretase activity in specific brain regions is not well understood, it is known that this dysfunctional enzymatic activity results in progressive dendritic pruning, neuronal loss and damage with marked cognitive decrements over time.
A problem with orally administered indomethacin or other nonsteroidal anti-inflammatory drugs is unpleasant side effects including severe nausea and gastric ulcers which patients develop following chronic use. Further, with chronic oral therapy the therapeutic value diminishes over time requiring dose escalation. In addition, limited transport of indomethacin or other nonsteroidal anti-inflammatory drugs across the blood brain barrier increases the potential for systemic adverse side-effects.
In order to maintain the same therapeutic affect with disease progression, the dose of indomethacin taken orally must increase. In patients having adverse side-effects, treatment escalation is not possible. Thus, oral administration of drugs such as indomethacin is inherently dose-limiting.
In addition to the problems just mentioned with orally administered indomethacin or similar nonsteroidal anti-inflammatory drugs, the amount of drug entering the patient""s blood system is minimized by uptake of the drugs by the gastrointestinal system.
It is therefore desirable to produce a chronic treatment regimen allowing the direct delivery of indomethacin or similar nonsteroidal anti-inflammatory drugs, having therapeutic value against the affect of amyloidogenic protein neurotoxicity, to the desired area of the brain. Such a treatment regimen is necessary to by-pass the adverse side-effects produced by orally administered drug and subsequent drug receptor uptake by the gastrointestinal system.
A method of treatment for Alzheimer""s disease is disclosed. The method comprises delivering indomethacin or similar nonsteroidal anti-inflammatory drugs through an implanted catheter positioned directly into the hippocampus with a delivery catheter attached to a drug delivery pump containing the therapeutic drug. The catheter has a flexible distal end that is implanted directly in the hippocampus. Alternatively, the distal end of the catheter may be positioned within the lateral ventricles of the cerebroventricular system which communicates anatomically via the inferior horn of the lateral ventricle immediately adjacent to the hippocampus.
The distal end has either a porous tip or a closed end. Where the distal end is closed, or a plurality of elution holes are present. Indomethacin or a similar drug is delivered to the hippocampus directly or indirectly via the cerebroventricular system. A pump is coupled to the catheter for delivery of the drug at a selected infusion rate. The combination of a catheter implanted directly in the brain and a pump to pump the drug through the catheter and out the distal end of the catheter into the brain allows direct access across the blood brain barrier. Thus, less drug is required for the desired therapeutic affect compared to oral or systemic delivery since drug is targeted within the central nervous system. Further, drug delivery directly to the brain limits drug access into the systemic circulation preventing access to secondary therapeutic targets associated with adverse side-effects associated with oral or systemic drug delivery.
The catheter preferably comprises a first tubular portion that has a generally cylindrical lumen of a first internal diameter and is composed of a relatively impermeable flexible material. A second tubular portion has an open end disposed within the lumen and a closed distal end disposed without the lumen. The second tubular portion is composed of a flexible, porous material having a preselected microporosity that is operable to permit the therapeutic drug, for example indomethacin, to flow from the catheter into the hippocampus. The second tubular portion is selectively moveable with respect to the first tubular portion.
Alternatively, a catheter for delivering indomethacin or a similar drug to a selected site within the hippocampus comprises a tubular portion composed of a relatively impermeable material. The distal end of the tubular portion is closed and has one or more elution holes through which indomethacin contained within the tubular portion exits the catheter.
It is therefore an object of the invention to provide a method and device for treating Alzheimer""s disease.
It is another object of the invention to administer indomethacin or another similar drug more effectively to the brain.
It is another object of the invention to administer indomethacin or another similar drug directly to the area of interest in the brain.
It is another object of the invention to administer indomethacin or another similar drug in tightly controlled amounts to the brain.
It is another object of the invention to administer indomethacin or another similar drug in minute dosages over time to the brain.
It is another object of the invention to continuously administer indomethacin or another similar drug over time to the brain.
It is another object of the invention to administer indomethacin or another similar drug over time to the hippocampus in the brain.
It is another object of the invention to administer indomethacin or another similar drug over time to the lateral ventricles in the brain.
It is another object of the invention to administer indomethacin or another similar drug over time to the marginal aspects of the lateral ventricles in the brain.
It is another object of the invention to administer indomethacin or another similar drug to the brain directly across the blood brain barrier.
These objects and advantages of the invention, as well as others that will be clear to those skilled in the art, will become apparent upon reading the following detailed description and references to the drawings. In the drawings and throughout this disclosure, like elements wherever referred to, are referenced with like reference numbers.